Programmed cell death (apoptosis) is integral to the sustenance of life as the constant renewal of tissue provides the physiologic scaffold for regenerative metabolism. Apoptosis facilitates the homeostatic balance of cellular renewal allowing for overall tissue health, so that the integrity of proliferative, immunomodulatory, and angiogenic components of tissue metabolism are maintained. A dysregulation in any one of, or a combination of, the aforementioned processes may result in a lack of apoptotic control. Such lack of apoptotic control, optionally in combination with genetic mutations, may result in a favorable oncogenic environment.
Under healthy conditions, the genome's “watchman,” p53, recognizes when a cell's integrity is compromised and commits it to apoptosis via employment of the Bcl-2 protein family in the mitochondria leading to nuclear fragmentation. See, e.g., Selivanova, at al., “Reactivation of mutant p53: molecular mechanisms and therapeutic potential,” Oncogene (2007) 26, 2243-2254.
Moreover, the balance of the “pro” and “anti” apoptotic members of the Bcl-2 protein family may determine the overall apoptotic potential for a cell. In over 60% of all cancers, p53 is mutated or inactivated and the Bcl-2 protein is overexpressed, leading to a resistance to cell death and chemotherapeutic approaches.
It has been shown that cancer patients have an overall decreased serum level of CoQ10 which may lead to sign and symptoms of malaise, weakness, and lethargy, especially when using chemotherapeutic modalities. See, e.g., Okamoto, et al. “Serum levels of coenzyme Q10 and lipids in patients during total parenteral nutrition,” J Nutr Sci Vitaminol (Tokyo), (1986) February; 32(1):1-12. Studies from the University of Miami using an athymic mouse model have demonstrated that a liposomal formulation of CoQ10 reduced human melanoma tumors by 53.2% in 30 days while an overall attenuation of tumor angiogenesis was observed. See, e.g., Persaud, et al., “Attenuation of tumor angiogenesis in murine melanoma model using liposomal formulation of Coenzyme Q10,” Proceedings of the American Association for Cancer Research, (2006); 47:A977. In addition, it was subsequently shown that the effect of CoQ10 was mediated by a downregulation of the Bcl-2 protein. See, e.g., Narain, et al., “Coenzyme Q10: A novel Bcl-2 drug target for the treatment of melanoma,” Proceedings of the American Association for Cancer Research, (2006); 47:A791.
Drugs have been developed to target the Bcl2 protein family either by direct antibody inhibition or by the use of specific constructs that interfere with binding, which may lead to dimerization or oligomerization, in an effort to restore the balance of the pro- and anti-apoptotic proteins. See, e.g., U.S. Pat. Nos. 6,514,761 and 6,040,181. However, this does not fundamentally alter the upstream levels of the major apoptotic members of the Bcl-2 protein family, such as Bcl-2, Bax, and Bid, following a re-activation of p53 which enables the given cell to undergo apoptosis.